In making connections from cellular genome to proteome to physiology, scientists have run up against many challenging computational problems, of which the least well understood is the "last step," from complex networks of interacting proteins to the regulated behavior of intact cells. The purpose of this proposal is to improve the computational tools for deriving the physiology of a cell from its internal molecular machinery, to integrate these tools into effective "problem-solving environments," to make these environments accessible to the international community of experimental and computational biologists, and to train a new generation of scientists in negotiating the last step of molecular cell biology. Our strategy is to develop a problem-solving environment for a specific application (regulation of the cell division cycle in eukaryotes), in collaboration with a number of groups who are working on more general computational platforms for "last-step" inquiries. We intend to create the first, fully functional environment for cell cycle modeling, incorporating sophisticated computational tools in data mining, model development, simulation, dynamical systems theory, data analysis and parameter estimation. Our software will be web-accessible, where it will serve as a powerful tool for the worldwide research community studying the regulation of mammalian cell proliferation. The cell-cycle problem-solving environment can then serve as a template for other environments specific to signaling, development, movement, and other basic properties of living cells. The proposal brings together some of the principal players in this arena: cell cycle modelers (Tyson, Novak and Chen), a team of computer scientists experienced in high-performance computing, problem-solving environments, and data mining (Watson, Shaffer, Kafura, Ramakrishnan), the author of Gepasi (Mendes at the Virginia Bioinformatics Institute), the "Virtual Cell" team (under Loew at U. Conn.), and some outstanding collaborators (Sible and Cross, experimental cell cycle research; Kitano and Bolouri, software development for molecular cell biology; and Kohn, bioinformatics of mammalian cell cycle controls).